This invention relates to the modulation and/or inhibition of cell signaling, cell proliferation, the control of abnormal cell growth and cell inflammatory response. More specifically, this invention relates to the use of mono- and/or bicyclic aryl or heteroaryl quinazoline compounds which exhibit selective inhibition of differentiation, proliferation or mediator release by effectively inhibiting CSF-1R tyrosine kinase activity.
Normal cell growth is believed to be triggered by the exposure of the cellular substrate to one or more growth factors, examples of which are insulin, epidermal growth factor (EGF) and platelet-derived growth factor (PDGE). Receptors for such growth factor are imbedded in and penetrate through the cellular membrane. The initiation of cellular reproduction is believed to occur when a growth factor binds to the corresponding receptor on the external surface of the cellular membrane. This growth factor-receptor binding alters the chemical characteristics of that portion of the receptor which exists within the cell and which functions as an enzyme to catalyze phosphorylation of either an intracellular substrate or the receptor itself, the latter being referred to as autophosphorylation. Examples of such phosphorylating enzymes include tyrosine kinases, which catalyze phosphorylation of tyrosine amino acid residues of substrate proteins.
Many disease states are characterized by the uncontrolled growth of cells. These disease states involve a variety of cell types and include disorders such as cancer, leukemia, psoriasis, inflammatory diseases, bone diseases, atherosclerosis and restenosis occuring subsequent to angioplastic procedures. The inhibition of tyrosine kinases is believed to have utility in the control of deregulated cellular proliferation, i.e., cellular proliferative disorders.
Initiation of autophosphorylation, i.e., phosphorylation of the growth factor receptor itself, and of the phosphorylation of a host of intracellular substrates are some of the biochemical events which are involved in mediator release and cell proliferation.
Inhibitors of p56Ick tyrosine kinase have been reported in the literature by Bolen, J. B. et al. FASEB J. 1992, 3403., Mustelin, T. et al. TIBS 1993 , 215.; Eichmann, K. Angew. Chem. Int. Ed. Eng. 1993, 54.; and Klausner, R. D. Samelson, L. E. Cell 1991 , 875. These include compounds that are potent but nonselective inhibitors, such as staurosporine, which is competitive with ATP or compounds that are very weak tyrosine kinase inhibitors, but are somewhat selective, such as the flavonoid quercetin.
A series of dihydroxy-isoquinolines have been been reported by Burke, T. R. et al. (Biorg. and Med. Chem. Lett. 1992, 1771; J. Med. Chem. 1993 3010 and J. Med. Chem. 1993 , 3015) that have potent p56Ick inhibiting activity. Potential therapeutic uses for selective inhibitors of p56Ick include the treatment of autoimmune diseases such as rheumatoid arthritis or transplant rejection.
p56Ick, which is a non-receptor tyrosine kinase, has been shown to be important in intracellular signaling in T-cells. It is assumed that inhibitors of p56Ick kinase activity perturb the activation of T-cells and therefore a selective inhibitor could prove useful in the treatment of T-cell mediated conditions such as organ rejection, rheumatoid arthritis or other auto-immune diseases.
The present invention describes compounds which are inhibitors of the colony stimulating factor-1 receptor tyrosine kinase, CSF-1R, activity and have activity in a p56Ick cell-free assay. These compounds do not appear to have any significant serine/threonine kinase inhibitory activity and in addition, compounds within the scope of this invention do not demonstrate significant PDGF-R activity in a cell-free assay. Compounds of this invention are also weak inhibitors of PDGF-induced mitogenesis which may suggest that these compounds inhibit other sic-like tyrosine kinases involved in the signal transduction pathway.
Compounds within the scope of this invention are inhibitors of the colony stimulating factor-1 receptor tyrosine kinase, CSF-1R, activity. A selective inhibitor of the tyrosine kinase activity of this receptor, which is closely related to the platelet-derived growth factor receptor (PDGF-R), has never been reported. Compounds of this invention are selective inhibitors of CSF-1R tyrosine kinase activity and are useful for elucidating the importance of CSF-1 and CSF-1 receptor signaling in bone remodeling and hematopoeisis. In addition compounds inhibiting growth factor-induced CSF and/or Ick signalling are described herein.
In accordance with the present invention, there is provided pharmaceutical compositions for inhibiting abnormal cell proliferation and/or differentiation or mediator release in a patient suffering from a disorder characterized by such proliferation activity, comprising the administration to a patient a tyrosine kinase composition which effectively inhibits CSF-1R tyrosine kinase activity in a CSF-1R inhibiting effective amount of a mono- aryl or heteroaryl quinazoline compound exhibiting inhibition of differentiation, proliferation or mediator release activity wherein each aryl group is a ring system containing 0-4 hetero atoms, said compound being optionally substituted or polysubstituted.
Another aspect of the present invention relates to a method of inhibiting abnormal cell proliferation and/or differentiation or mediator release comprising, in admixture with a pharmaceutically acceptable carrier, a pharmaceutically effective amount of a compound of the aforementioned type. Another aspect of this invention comprises compounds useful in the practice of the present method.
With respect to the aspects of this invention, the compounds described by Formula I below constitute a class of the aforementioned mono- and bicicyclic aryl or heteroaryl quinazoline compounds for use in the practice of the present invention: 
wherein
Ar is a substituted or unsubstituted mono- or bi-cyclic aryl or heteroaryl ring system of about 5 to about 12 atoms and where each monocyclic ring may contain 0 to about 3 hetero atoms, and each bicyclic ring may contain 0 to about 4 hetero atoms selected from N, O and S provided said hetero atoms are not vicinal oxygen and/or sulfur atoms and where the substituents may be located at any appropriate position of the ring system and are described by R.;
X is a bond, O, S, SO, SO2, OCH2, Cxe2x95x90C, Cxe2x89xa1C, Cxe2x95x90S, SCH2, NH, NHCH2, NR4 or NR4CH2;
R independently includes hydrogen, alkyl, alkenyl, phenyl, aralkyl, aralkenyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, aralkoxy, aryloxy, acyloxy, halo, haloalkyl, nitro, cyano, amino, mono- and di-alkylamino, acylamino, carboxy, carboxyalkyl, carbalkoxy, carbaralkoxy, carbalkoxyalkyl, carbalkoxyalkenyl, aminoalkoxy, amido, mono- and di-alkylamido and N,N-cycloalkylamido, alkylthio, alkylsulfinyl, sulfonyl, mono- and di-alkyl sulfonyl, sulfamoyl, mono- and di-alkyl sulfamoyl, halophenyl or benzoyl; and R and R together may also form a ketone group.
R4 is alkyl, xe2x80x94CH2xe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94; and
R5, R6 and R7 are independently hydrogen, alkyl, alkylthio, cycloalkyl, hydroxy, alkoxy, aralkoxy, aryl, halo, haloalkyl, carboxy or carbalkoxy; or
a pharmaceutically acceptable salt thereof.
Preferred Ar monocyclic aryl or heteroaryl rings include substituted or unsubstituted benzene, pyrrole, thiophene, furan, thiazole, imidazole, pyrazole, 1,2,4-triazole, pyridine, 2(1H)-pyridone, 4(1H)-pyridone, pyrazine, pyrimidine, pyridazine, isothiazole, isoxazole, oxazole and tetrazole.
Preferred Ar bicyclic aryl or heteroaryl rings include substituted and unsubstituted naphthalene, tetralin, naphthyridine, benzofuran, benzothiophene, indole, 2,3-dihydroindole, 1H-indazole, indoline, benzopyrazole, 1,3-benzodioxole, benzoxazole, purine, coumarin, chromone, quinoline, tetrahydroquinoline, isoquinoline, benzimidazole, quinazoline, pyrido[2,3-b]pyrazine, pyrido[3,4-b]pyrazine, pyrido[3,2-c]pyridazine, pyrido[3,4-b]-pyridine, 1H-pyrazole[3,4-d]pyrimidine, pteridine, 2(1H)-quinolone, 1(2H)-isoquinolone, 1,4-benzisoxazine, benzothiazole, quinoxaline, quinoline-N-oxide, isoquinoline-N-oxide, quinoxaline-N-oxide, quinazoline-N-oxide, benzoxazine, phthalazine, or cinnoline.
More preferred Ar rings include substituted and unsubstituted benzene, pyridine, thiophene, naphthalene, quinoline, indole and 1H-pyrazole[3,4-d]pyrimidine.
Preferred R substituents include hydrogen, alkyl, alkenyl, hydroxy, alkoxy, halo, haloalkyl, amino, mono-and di-alkylamino, acylamino, carboxy, carbalkoxy, amido, mono- and di-alkylamido, N,N-cycloalkylamido, alkylthio, alkylsulfinyl, alkylsulfonyl or sulfamoyl, alkyl, alkenyl, phenyl, aralkyl, aralkenyl, and R may also form a keto group.
As employed above and throughout this disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings:
xe2x80x9cMonocyclic aryl or heteroarylxe2x80x9d means a carbocyclic or heterocyclic aromatic ring. Preferred rings include phenyl, thienyl, pyridyl, 2(1H)-pyridonyl, 4(1H)-pyridonyl, furyl, pyrimidinyl, imidazolyl, thiazolyl, oxazolyl and tetrazolyl.
xe2x80x9cBicyclic aryl or heteroarylxe2x80x9d means a bicyclic ring system composed of two fused carbocyclic and/or heterocyclic aromatic rings. Preferred rings include naphthyl, indolyl, benzothienyl, benzofuranyl, quinolinyl, chromonyl, 1(2H)-isoquinolonyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, quinoxalinyl, naphthyridinyl, cinnolinyl, phthalazinyl, pyrido[2,3-b]pyrazinyl, pyrido[3,4-b]pyrazinyl, pyrido[3,2-c]pyridazinyl, pyrido[3,4-b]-pyridinyl, pteridinyl, and quinazolinyl.
xe2x80x9cAlkylxe2x80x9d means a saturated aliphatic hydrocarbon, either branched- or straight-chained. Preferred alkyl is xe2x80x9cloweralkylxe2x80x9d having about 1 to about 6 carbon atoms. Examples of alkyl include methyl, ethyl, n-propyl, isopropyl, butyl, sec-butyl, t-butyl, amyl and hexyl.
xe2x80x9cCycloalkylxe2x80x9d means a cyclic aliphatic group comprising from about three to about seven carbon atoms. Preferred cycloalkyl groups include cyclopropyl, cyclobutyl, cyclohexyl and cycloheptyl.
xe2x80x9cAlkoxyxe2x80x9d refers to an alkyl-O-group. Preferred alkoxy groups include methoxy, ethoxy, propoxy and butoxy.
xe2x80x9cAryloxyxe2x80x9d refers to an aryl-O-group. The preferred aryloxy group is phenoxy.
xe2x80x9cAralkylxe2x80x9d means an alkyl group substituted by an aryl radical. The preferred aralkyl groups are benzyl or phenethyl.
The preferred aralkoxy groups are benzyloxy and phenethoxy.
The preferred acyloxy groups are acetoxy and benzyloxy;
xe2x80x9cHaloxe2x80x9d means halogen. Preferred halogens include chloride, bromide and fluoride.
The preferred haloalkyl groups are mono-, di- and trifluoromethyl.
The more preferred compounds of this invention include those compounds of Formula I where
Ar is phenyl or naphthyl;
R is hydrogen, alkyl, alkoxy, hydroxy, halo or trifluoromethyl.
X is a bond, NH or NR4; and
R5, R6 and R7 are independently hydrogen or alkoxy.
The most preferred compounds are those described where
Ar is phenyl;
X is NH or NMe; and
R5, R6 and R7 are independently hydrogen or methoxy.
It is intended that N-oxides of the above described aminoquinazolines are encompassed within the scope of this invention.
Special embodiments of this invention inhibiting the growth factor or tyrosine kinase include the following:
A. Compounds of Formula I where:
X is a bond, NR4, S or O, the inhibiting cell proliferation and/or differentiation or mediator release is especially characterized by CSF-1 activity.
B. Compounds of Formula I where:
X is a bond, NH, S or O, the inhibiting cell proliferation and/or differentiation or mediator release is especially characterized by Ick/EGF activity.
C. Compounds of Formula I where:
X is a bond and Ar is phenyl, indolyl, pyrrolyl, thienyl, pyridyl, naphthyl, a bicyclic aryl, a bicyclic heteroaryl or substituted phenyl, indolyl, pyrrolyl, thienyl, pyridyl, naphthyl, bicyclic aryl, bicyclic heteroaryl, the inhibiting cell proliferation and/or differentiation or mediator release is especially characterized by Ick activity.
D. Compounds of Formula I where:
X is NH, R6 and R7 are alkoxy and Ar is phenyl having at least one substituent in the 3, 4 and/or 5 positions of hydroxy or alkoxy, the inhibiting cell proliferation and/or differentiation or mediator release is especially characterized by Ick activity.
The compounds of this invention may be useful in the form of the free base, in the form of salts and as a hydrate. All forms are within the scope of the invention. Acid addition salts may be formed and are simply a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the base form. The acids which can be used to prepare the acid addition salts include preferably those which produce, when combined with the free base, pharmaceutically acceptable salts, that is, salts whose anions are non-toxic to the animal organism in pharmaceutical doses of the salts, so that the beneficial properties inherent in the free base are not vitiated by side effects ascribable to the anions. Although pharmaceutically acceptable salts of said basic compound are preferred, all acid addition salts are useful as sources of the free base form even if the particular salt per se is desired only as an intermediate product as, for example, when the salt is formed only for purposes of purification and identification, or when it is used as an intermediate in preparing a pharmaceutically acceptable salt by ion exchange procedures.
Pharmaceutically acceptable salts within the scope of the invention include those derived from the following acids: mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid and sulfamic acid; and organic acids such as acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, quinic acid, and the like.
The corresponding acid addition salts comprise the following: hydrochloride, sulfate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate, respectively.
The acid addition salts of the compounds of this invention are prepared either by dissolving the free base in aqueous or aqueous-alcohol solution or other suitable solvents containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.
The compounds of this invention may be prepared by employing procedures known in the literature starting from known compounds or readily prepared intermediates. Exemplary general procedures follow.
In general the compounds useful for the method of inhibiting cell proliferation and/or differentiation or mediator release may be prepared by the coupling reaction of a palladium catalyzed aryl or heteroarylstannane with an aryl or heteroarylhalide or triflate. 
where A is halogen or triflate and B is trialkylstannane and R is as previously described.
The 4-haloquinazoline starting materials are prepared in the classical way using anthranilic acid derivatives and formamide at reflux to provide the intermediate quinazolinones. Subsequent treatment with POCl3 at about 110xc2x0 C. for about two hours provides the chloroquinazolines. The final products are prepared via a condensation with the appropriate aniline derivative in a polar solvent such as ethanol. In the case of the phenoxy or thiophenoxy derivatives, the metal salt (preferably Na) is prepared and refluxed for several hours with the appropriate haloquinazoline in a solvent such as THF. 
The aryl and heteroarylstannanes may be prepared from the corresponding halide (preferably bromide or iodide) by conversion to the aryllithium by reaction with t-butyllithium at decreased temperatures, preferably about xe2x88x9278xc2x0 C. followed by reaction with a halotrialkylstannane. 
Of course these products may also be prepared in the reverse manner using the aryl or heteroarylhalides with the the corresponding stannane. 
The quinazoline stannanes intermediates may be prepared by the action of trimethyltin sodium on aryl halides as described in Chem. Pharm. Bull. 1982, 30, 1731-1737:
The preparation of the compounds useful in this invention are described in Applicants"" copending applications U.S. Ser. No. 08/166,199, filed Dec. 10, 1993 and U.S. Ser. No. 08/229,886, filed Apr. 19, 1994 of which this application claims priority. U.S. Ser. No. 08/166,199 and U.S. Ser. No. 08/229,886 are hereby incorporated herein by reference.
Further, the following examples are representative of the processes used to synthesis the compounds of this invention.